Correction: Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients.

[This corrects the article DOI: 10.1371/journal.pone.

Myrtleciclib, a CDK4/6/9 Inhibitor for the Treatment of Aggressive Cancers.

Background: Selective Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of breast cancer and have potential in other cancers, being manageable drugs yet with some bone marrow toxicity. Selective CDK9 inhibitors (CDK9i) never advanced into clinical use, partly due to side effects, including gastrointestinal toxicity, and a small window between activity and cytotoxicity, which results in a narrow therapeutic index (TI).

Method: To overcome the drawbacks of CDK4/6 and CDK9 inhibitors, we have developed myrtleciclib, a selective CDK4/6/9 inhibitor with few non-critical molecular off-targets.

In Vitro Antiviral Activity of Hyperbranched Poly-L-Lysine Modified by L-Arginine against Different SARS-CoV-2 Variants.

The emergence of SARS-CoV-2 variants requires close monitoring to prevent the reoccurrence of a new pandemic in the near future. The Omicron variant, in particular, is one of the fastest-spreading viruses, showing a high ability to infect people and evade neutralization by antibodies elicited upon infection or vaccination. Therefore, the search for broad-spectrum antivirals that can inhibit the infectious capacity of SARS-CoV-2 is still the focus of intense research.

Reply to Taylor et al. Comment on "Manna et al. SARS-CoV-2 Inactivation in Aerosol by Means of Radiated Microwaves. 2023, , 1443".

SARS-CoV-2 is inactivated in aerosol (its primary mode of transmission) by means of radiated microwaves at frequencies that have been experimentally determined. Such frequencies are best predicted by the mathematical model suggested by Taylor, Margueritat and Saviot. The alignment between such mathematical prediction and the outcomes of our experiments serves to reinforce the efficacy of the radiated microwave technology and its promise in mitigating the transmission of SARS-CoV-2 in its naturally airborne state.

SARS-CoV-2 Inactivation in Aerosol by Means of Radiated Microwaves.

Coronaviruses are a family of viruses that cause disease in mammals and birds. In humans, coronaviruses cause infections on the respiratory tract that can be fatal. These viruses can cause both mild illnesses such as the common cold and lethal illnesses such as SARS, MERS, and COVID-19.

Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients.

Despite new antivirals are being approved against SARS-CoV-2 they suffer from significant constraints and are not indicated for hospitalized patients, who are left with few antiviral options. Repurposed drugs have previously shown controversial clinical results and it remains difficult to understand why certain trials delivered positive results and other trials failed. Our manuscript contributes to explaining the puzzle: this might have been caused by a suboptimal drug exposure and, consequently, an incomplete virus suppression, also because the drugs have mostly been used as add-on monotherapies.

Effective SARS-CoV-2 antiviral activity of hyperbranched polylysine nanopolymers.

The coronavirus pandemic (COVID-19) had spread rapidly since December 2019, when it was first identified in Wuhan, China. As of April 2021, more than 130 million cases have been confirmed, with more than 3 million deaths, making it one of the deadliest pandemics in history. Different approaches must be put in place to confront a new pandemic: community-based behaviours (, isolation and social distancing), antiviral treatments, and vaccines.

Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug-Resistant HIV-1 Strains.

HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of the HIV-1 life cycle are efficient in blocking viral replication but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets.

Exploitation of Langerhans cells for in vivo DNA vaccine delivery into the lymph nodes.

There is no clinically available cancer immunotherapy that exploits Langerhans cells (LCs), the epidermal precursors of dendritic cells (DCs) that are the natural agent of antigen delivery. We developed a DNA formulation with a polymer and obtained synthetic 'pathogen-like' nanoparticles that preferentially targeted LCs in epidermal cultures. These nanoparticles applied topically under a patch-elicited robust immune responses in human subjects.

Safety, tolerability, and immunogenicity of repeated doses of dermavir, a candidate therapeutic HIV vaccine, in HIV-infected patients receiving combination antiretroviral therapy: results of the ACTG 5176 trial.

Background: HIV-specific cellular immune responses are associated with control of viremia and delayed disease progression. An effective therapeutic vaccine could mimic these effects and reduce the need for continued antiretroviral therapy. DermaVir, a topically administered plasmid DNA-nanomedicine expressing HIV (CladeB) virus-like particles consisting of 15 antigens, induces predominantly central memory T-cell responses.

VS411 reduced immune activation and HIV-1 RNA levels in 28 days: randomized proof-of-concept study for antiviral-hyperactivation limiting therapeutics.

Background: A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects.

Single DermaVir immunization: dose-dependent expansion of precursor/memory T cells against all HIV antigens in HIV-1 infected individuals.

Background: The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART).

Methodology/principal Findings: This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen HIV antigens in draining lymph nodes: 0.1 mg DNA targeted to two, 0.

DermaVir: a plasmid DNA-based nanomedicine therapeutic vaccine for the treatment of HIV/AIDS.

The HIV global pandemic continues to rage with over 33 million people living with the disease. Although multidrug therapy has improved the prognosis for those infected by the virus, it has not eradicated the infection. Immunological therapies, including therapeutic vaccines, are needed to supplement drug therapy in the search for a 'functional cure' for HIV.

Amplified antigen-specific immune responses in HIV-1 infected individuals in a double blind DNA immunization and therapy interruption trial.

Immunotherapy in patients with HIV-1 infection aims to restore and broaden immunological competence, reduce viral load and thereby permit longer periods without combined antiretroviral treatment (cART). Twelve HIV-1-infected patients on cART were immunized on the skin with DNA plasmids containing genes of several HIV-1 subtypes with or without the addition of hydroxyurea (HU), or with placebo. The mean net gain of HIV-specific CD8+ T cell responses were higher and broader in the HIV DNA vaccine groups compared to non-vaccinated individuals (p<0.

A plasmid DNA immunogen expressing fifteen protein antigens and complex virus-like particles (VLP+) mimicking naturally occurring HIV.

We describe here a single plasmid DNA immunogen representing the broadest antigen repertoire among HIV vaccine candidates. This pDNA was "ANTIGENeered" for the regulated expression of thirteen complete and two non-functional HIV protein antigens. These proteins self assemble into complex virus-like particles (VLP(+)).

Strategies to improve efficacy and safety of a novel class of antiviral hyper-activation-limiting therapeutic agents: the VS411 model in [corrected] HIV/AIDS.

Background And Purpose: Antiviral hyper-activation-limiting therapeutic agents (AV-HALTs) are a novel experimental drug class designed to both decrease viral replication and down-regulate excessive immune system activation for the treatment of chronic infections, including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first-in-class AV-HALT, is a single-dosage form combining didanosine (ddI, 400 mg), an antiviral (AV), and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (C(max)) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity.

Experimental Approach: This was a pilot phase I, open-label, randomized, single-dose, four-way crossover trial to investigate the fasted and non-fasted residual variance of AUC, C(max) and the oral bioavailability of ddI and HU, co-formulated as VS411, and administered as two different fixed-dose combination formulations compared to commercially available ddI (Videx EC) and HU (Hydrea) when given simultaneously.

Heritability and demographic analyses in the large isolated population of Val Borbera suggest advantages in mapping complex traits genes.

Background: Isolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South.

Methodology/principal Findings: The study involved 1,803 people living in 7 villages of the upper Borbera Valley.

Treating HIV/AIDS by reducing immune system activation: the paradox of immune deficiency and immune hyperactivation.

Purpose Of Review: To collect published evidence in support of a novel immune therapeutic approach to reduce the excess of immune activation that ultimately turns into immune deficiency in HIV/AIDS.

Recent Findings: A large body of evidence has been collected in support of the pathogenetic interpretation that prolonged immune overactivation induced by HIV during the course of chronic infection exhausts the immune system and leads to AIDS. Some groups are exploring the possibility of therapeutic interventions to limit the immune system overload.

Beneficial effect of TRAIL on HIV burden, without detectable immune consequences.

Background: During uncontrolled HIV disease, both TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptor expression are increased. Enhanced TRAIL sensitivity is due to TRAIL receptor up-regulation induced by gp120. As a result of successful antiretroviral therapy TRAIL is down-regulated, and there are fewer TRAIL-sensitive cells.

IL-15 as memory T-cell adjuvant for topical HIV-1 DermaVir vaccine.

IL-7 and IL-15 are key cytokines involved in the generation and maintenance of memory CD8+ T-cells. We evaluated these cytokines as molecular adjuvants for topical HIV-1 DermaVir vaccine. We found that mice receiving DermaVir formulated with HIV-1 Gag plasmid in the presence of IL-7- or IL-15-encoding plasmid significantly enhanced Gag-specific central memory T-cells, as measured by a peptide-based cultured IFN-gamma ELISPOT.

HIV-1-specific T cell precursors with high proliferative capacity correlate with low viremia and high CD4 counts in untreated individuals.

Evidences have recently suggested that the preservation of vaccine-induced memory rather than effector T cells is essential for better outcome and survival following pathogenic SIV challenge in macaques. However, an equivalent demonstration in humans is missing, and the immune correlates of HIV-1 control have been only partially characterized. We focused on the quantification of Ag-specific T cell precursors with high proliferative capacity (PHPC) using a peptide-based cultured IFN-gamma ELISPOT assay (PHPC assay), which has been shown to identify expandable memory T cells.

A checkpoint in the cell cycle progression as a therapeutic target to inhibit HIV replication.

Human immunodeficiency virus (HIV) expression is boosted after T lymphocyte stimulation. It is not known, however, in which phase(s) of the cell cycle HIV is maximally expressed. We demonstrate here that cell activation induces limited HIV expression and that progression to cell proliferation is required for optimal HIV replication.

The potential of topical DNA vaccines adjuvanted by cytokines.

To improve the efficacy of DNA immunization epidermal Langerhans cells are attractive targets to deliver antigen-encoding plasmid DNA. Topical vaccination with naked plasmid DNA has been shown to induce immune responses, and their potency might be improved by chemical and physical methods aimed to enhance the efficiency of plasmid DNA delivery into the skin. Cytokines have also been evaluated as adjuvants for DNA vaccines because they influence the host immune response.